16-2080299-C-G

Position:

• chr16-2080299-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000548.5(TSC2):​c.3532C>G​(p.Gln1178Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Q1178Q) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.59

Genes affected

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11943409).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.3532C>G	p.Gln1178Glu	missense_variant	30/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.3532C>G	p.Gln1178Glu	missense_variant	30/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74376

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 08, 2023	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 1178 of the TSC2 protein (p.Gln1178Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 207746). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2016

This variant is denoted TSC2 c.3532C>G at the cDNA level, p.Gln1178Glu (Q1178E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. TSC2 Gln1178Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. TSC2 Gln1178Glu occurs at a position that is not conserved and is not located in a known functional domain (Gumbinger 2009). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether TSC2 Gln1178Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2022

The p.Q1178E variant (also known as c.3532C>G), located in coding exon 29 of the TSC2 gene, results from a C to G substitution at nucleotide position 3532. The glutamine at codon 1178 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	12
DANN	Benign	0.29
DEOGEN2	Benign	0.40	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.7	L;.;.;.;.;.;.;.;.;L;.;.;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.86	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.54
Sift	Benign	0.48	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.66	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.0020	B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.44
MutPred		0.26		Loss of methylation at K1180 (P = 0.0809);.;Loss of methylation at K1180 (P = 0.0809);.;.;.;.;Loss of methylation at K1180 (P = 0.0809);.;Loss of methylation at K1180 (P = 0.0809);.;.;.;.;.;
MVP		0.95
ClinPred		0.021	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs45517297; hg19: chr16-2130300;